EDITORIAL COMMENT
Vasodilator Therapy for Decompensated Heart Failure*
Clyde W. Yancy, MD, FACC, FAHA, FACP*
Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, Texas.
* Reprint requests and correspondence: Dr. Clyde W. Yancy, Baylor University Medical Center, Baylor Heart and Vascular Institute, 3500 Gaston Avenue, Suite H-030, Dallas, Texas 75246. (Email: clydey{at}baylorhealth.edu).
What was once old is now new again—Author unknown
Sodium nitroprusside (SNP) has been available as a parenteral agent in cardiovascular medicine for >30 years. It exists as a dianion [Fe(CN)5NO]2– in which the iron moiety is an octahedral surrounded by 5 cyanide ligands and 1 nitric oxide ligand. Its mechanism of action is the liberation of nitric oxide, which is accompanied by the release of cyanide ions (1).
Sodium nitroprusside is appropriate for the acute treatment of congestive heart failure. The starting dose is 0.3 to 0.5 µg/kg/min titrated to goal attainment of desired hemodynamics but usually not beyond 5 µg/kg/min. Doses of 10 µg/kg/min or sustained administration will result in excessive cyanide production, which may occasionally lead to cyanide poisoning and may rarely lead to the development of methemoglobinemia. Both conditions require immediate intervention with cessation of the infusion and/or initiation of hemodialysis and possibly administration of thiosulfate or methylene blue. When used for heart failure, placement of a right heart catheter is appropriate to monitor the response to SNP therapy. Given these several circumstances, the use of this older drug has yielded to newer treatments for heart failure (2).
In this issue of the Journal, Mullens et al. (3) have published their experience regarding the use of SNP for the management of advanced decompensated heart failure. These retrospective, single-center, nonrandomized data represent the first recent database to revisit the potential salutary benefits of SNP as vasoactive therapy in the setting of decompensated heart failure. The data were obtained in a highly selected patient cohort characterized by advanced heart failure with low cardiac output and increased vascular resistance. The adjunctive use of SNP yielded an excellent acute hemodynamic response and was associated with a neutral, if not favorable, intermediate term effect when the acute use of SNP was followed by optimal use of evidence-based medical therapy, including oral vasodilator therapy. Specifically, the use of isosorbide dinitrate and hydralazine in addition to angiotensin-converting enzyme I or angiotensin-receptor blocker plus beta-blocker increased from 26% or 16%, respectively, at admission to 48% for combined vasodilator therapy at discharge. It is provocative to view these findings in context with other data (i.e., A-HeFT [African American Heart Failure Trial]) as further evidence that nitric oxide bioavailability is important in heart failure (4).
As noted in the Heart Failure Society of America 2006 Comprehensive Heart Failure Practice Guideline, the use of 1 of 3 vasodilators—nitroglycerin, sodium nitroprusside, or nesiritide—is prompted, that is, "may be considered," for acute decompensated heart failure (ADHF) with symptoms at rest in the absence of hypotension when acute relief of dyspnea is a goal of therapy (5). These compounds are intended to be given as adjunctive therapy for background diuretic therapy. The use of vasodilator therapy, specifically nitroglycerin and nesiritide, has been associated with an immediate reduction in filling pressures and relief of dyspnea (6), but certain safety questions regarding nesiritide have been noted (7,8). Newer agents, such as arginine-vasopressin antagonists, with vasodilator properties have also demonstrated a prompt reduction of filling pressures, relief of dyspnea, and sustained weight loss consistent with decongestion (9,10). To date, however, none of these agents has been associated with an improvement in outcomes of ADHF. Importantly, the data supporting SNP emanate not from clinical trial data but principally from >30 years of clinical use by experienced physicians, that is, from "consensus opinion."
Early data from Cohn and Burke (11) introduced the rationale for vasodilation in heart failure. Subsequently, Stevenson (12) helped to establish the benefit of SNP in patients with advanced heart failure—specifically, transplant-eligible patients with New York Heart Association functional class IV symptoms and a phenotype of increased vascular resistance and marginal cardiac output. In patients instrumented with a right heart catheter, SNP was used to effect "tailored therapy" with targeted goal reductions in pulmonary capillary wedge pressure, central venous pressure, and systemic vascular resistance while preserving blood pressure and achieving an adequate cardiac index. Once certain hemodynamic targets were reached, conversion to oral therapy ensued. For those patients with advanced heart failure, the attainment of tailored therapy goals yielded a 1-year survival that was equivalent to the prevailing 1-year survival after transplant (12). Sodium nitroprusside also has an indication for hypertensive emergency (13,14), may be paradoxically beneficial for critical aortic stenosis (14), and facilitates the management of acute aortic or mitral insufficiency where prompt afterload reduction results in hemodynamic stabilization.
Despite this portfolio of efficacy for several cardiovascular disease states, the use of SNP has been relegated to a historical footnote. Why has this occurred when the benefit in several clinical scenarios is apparent, the safety profile is manageable, and the magnitude of its acute efficacy for decompensated heart failure is possibly greater than other parenterally administered compounds? As a generic compound, there is no marketing effort for SNP; the requirement for invasive hemodynamic monitoring is a very legitimate hindrance; and the real but infrequent risk of cyanide toxicity generates concern. However, perhaps it is time to revive this older agent as a "new" modality for certain patients with decompensated heart failure.
Recently, the best synthesis of the pathophysiology of acute decompensated heart failure has been a hemodynamic definition based on evidence of congestion, that is, increased preload (15,16). This concept does not identify the correct biological pathophysiology, and indeed, the heterogeneity of ADHF would suggest that multiple basic mechanisms are likely operative and several may be correlative. The narrowing of our hemodynamic construct to consider congestion as the primary hemodynamic malady in ADHF is not unwarranted. However, the extension of that concept to specifically implicate volume overload has yielded an overbearing emphasis on "decongestion," which is usually accomplished with diuretic administration that is sometimes given in considerable doses with increasing evidence that such may not be entirely without risk.
A more comprehensive description of the pathophysiology of ADHF might focus instead on left and/or right atrial hypertension with volume overload as only 1 of the contributors to this hemodynamic perturbation. By focusing on atrial hypertension, a more global appreciation of the myriad of hemodynamic models in ADHF could be considered. Specifically, increased afterload with concomitant low or marginal cardiac outputs, abnormal left/right ventricle compliance, and significant atrioventricular valvular regurgitation are all plausible explanations for ADHF that vary from a volume overload model. Of these additional hemodynamic profiles, diuretic therapy alone is not likely to be of sufficient benefit. However, the selective use of vasodilator therapy, in conjunction with a regimen of decongestion, more appropriately addresses this broader spectrum of hemodynamic disruptions in ADHF. See Figure 1
for a proposed broader based treatment algorithm for ADHF.
View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Pathophysiology and Treatment of Decompensated Heart Failure
The chart shows the pathophysiology and treatment of decompensated heart failure. Category D includes diuretics, aquaretics, and adenosine antagonists' (under investigation) mechanical volume removal, for example, ultrafiltration. Category V includes vasodilators such as nitroglycerin, sodium nitroprusside, or nesiritide, and also considers arginine-vasopressin antagonists. Category I includes inotropes including catecholamines, phosphodiesterase inhibitors, Ca++ sensitizers, myosin activators (under investigation), and percutaneous left ventricular assist devices (if eligible for a transplant or a left ventricular assist device). BP = blood pressure; EDP = end-diastolic pressure; HF = heart failure; HTN = hypertension; PCWP = pulmonary capillary wedge pressure; RA = right atrium; SVR = systemic vascular resistance.
|
|
The current data by Mullens et al. (3) buffet this broader view of decompensated heart failure. For those patients with advanced heart failure and borderline systemic blood pressure in whom a reasonable indication exists for right heart catheterization, a hemodynamic profile of marginal cardiac output, high filling pressures, and elevated systemic vascular resistance or peripheral vascular resistance should prompt consideration for diuretics plus vasodilator therapy. Based on the present data, SNP is a reasonable option for these patients. The outcome data from Mullens et al. (3) are provocative but should be taken with measured reserve. This is a highly selected patient population treated in a tertiary care center presumably with very appropriate outpatient follow-up. The observed "benefit" may indeed have been due to the use of SNP, but the impact of a structured disease management program, the adverse effect of any inotropic exposure in the control group, and the curious benefit of adjunctive isosorbide dinitrate/hydralazine (race neutral) mute any significant enthusiasm for a unique intermediate-term benefit of SNP. Such an observation should be reserved for findings from a larger prospective randomized controlled trial.
What are the lessons learned from this experience? - 1 Sodium nitroprusside is a reasonable therapeutic intervention in patients with advanced heart failure who are hospitalized with decompensation and have undergone right heart catheterization with evidence of a hemodynamic profile consistent with both increased preload (congestion) and increased afterload.
- 2 In experienced hands and for selected patients, right heart catheterization remains a reasonable diagnostic intervention and yields "biomarkers" appropriate to titration therapy.
- 3 Maximal use of evidence-based regimens for heart failure including combined vasodilator therapy (isosorbide dinitrate/hydralazine, race-irrespective) in the setting of careful medical management yields reasonable, if not good, outcomes even in patients with advanced heart failure.
- 4 There may be benefit of nitric oxide enhancement in both acute and chronic models of heart failure.
Several limitations must also be acknowledged: we remain without randomized multicenter data regarding the use of SNP for ADHF; the process of care delivery systems required to safely administer SNP and proceed with close pulmonary artery catheter/hemodynamic monitoring are very center-specific; the selection of patients for right heart catheterization is somewhat subjective; we do not have a reasonable noninvasive alternative to right heart catheterization; the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) study data (17) dissuading routine use of right heart catheterization are inescapable; and greater use of SNP is likely to be associated with an increase in the occurrence of cyanide toxicity—a potentially morbid complication. Yet, broader use of SNP now appears to be a more palatable consideration for patients with decompensated advanced heart failure.
While we continue to search for a treatment panacea for ADHF, we should perhaps recognize the hemodynamic complexity of the disease, broaden our hemodynamic model to include conditions of both increased preload and increased afterload, expand the treatment regimen to include a greater use of vasodilator therapy, and acknowledge that a drug older than most interns but tried and tested over several different eras of cardiovascular medicine may still be of considerable benefit for heart failure. It is possible that "what was once old is now new again" for ADHF.
 |
Footnotes
|
|---|
Dr. Yancy is a consultant for ARCA Discovery, Scios Inc., NitroMed, Medtronic, AstraZeneca, Otsuka, and GlaxoSmithKline. He receives or has received research support from GlaxoSmithKline, Scios Inc., NitroMed, and Medtronic, and financial or materials support from Medtronic and Scios Inc. He serves on the Speakers' Bureaus of GlaxoSmithKline and Novartis. Dr. Yancy is an Associate Editor for American Journal of Cardiology, and he is on the editorial boards of American Heart Journal, Cardiology Quarterly, Circulation, Congestive Heart Failure, and Urban Cardiology. He holds government appointments to the Food and Drug Administration (member, 2004 to 2006, circulatory devices panel; Chair, 2007 to 2008) and the National Heart, Lung, and Blood Institute (member, study section, clinical and integrative cardiovascular science).
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Nitroprusside (Systemic) Drugs.com [online database]http://www.drugs.com/mmx/nitroprusside-sodium.htmlAccessed February 25, 2008.2. RxList: The Internet Drug Indexhttp://www.rxlist.com/cgi/generic/nitroprusside_cp.htmAccessed February 25, 2008. 3. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-output heart failure J Am Coll Cardiol 2008;52:200-207.[Abstract/Free Full Text] 4. Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial Circulation 2007;115:1747-1753.[Abstract/Free Full Text] 5. Heart Failure Society of America HFSA 2006 Comprehensive Heart Failure Practice Guideline J Card Fail 2006;12:e1-e2.[CrossRef][Medline] 6. Publication Committee for the VMAC (Vasodilatation in the Management of Acuity CHF) Investigators Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial (erratum in JAMA 2002;288:577) JAMA 2002;287:1531-1540.[Abstract/Free Full Text] 7. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials JAMA 2005;293:1900-1905.[Abstract/Free Full Text] 8. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure Circulation 2005;111:1487-1491.[Abstract/Free Full Text] 9. Gheorghiade M, Konstam MA, Burnett Jr. JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials JAMA 2007;297:1332-1343.[Abstract/Free Full Text] 10. Konstam MA, Gheorghiade M, Burnett Jr. JC, et al. EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) Investigators Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial JAMA 2007;297:1319-1331.[Abstract/Free Full Text] 11. Cohn JN, Burke LP. Nitroprusside Ann Intern Med 1979;91:752-757.[Abstract/Free Full Text] 12. Stevenson LW. Tailored therapy before transplantation for treatment of advanced heart failure: effective use of vasodilators and diuretics J Heart Lung Transplant 1991;10:468-476.[Web of Science][Medline] 13. Elliott WJ. Management of hypertension emergencies Curr Hypertens Rep 2003;5:486-492.[CrossRef][Web of Science][Medline] 14. Popovic ZB, Khot UN, Novaro GM, et al. Effects of sodium nitroprusside in aortic stenosis associated with severe heart failure: pressure-volume loop analysis using a numerical model Am J Physiol Heart Circ Physiol 2005;288:H416-H423.[Abstract/Free Full Text] 15. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart failure syndromes: an essential target of evaluation and treatment Am J Med 2006;119:S3-S10.[Medline] 16. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research Circulation 2005;112:3958-3968.[Free Full Text] 17. Binanay C, Califf RM, Hasselbad V, et al. ESCAPE Investigators and ESCAPE Study Coordinators Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: the ESCAPE trial JAMA 2005;294:1625-1633.[Abstract/Free Full Text]
Related Article
-
Sodium Nitroprusside for Advanced Low-Output Heart Failure
- Wilfried Mullens, Zuheir Abrahams, Gary S. Francis, Hadi N. Skouri, Randall C. Starling, James B. Young, David O. Taylor, and W.H. Wilson Tang
J. Am. Coll. Cardiol. 2008 52: 200-207.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
N. L. Weintraub, S. P. Collins, P. S. Pang, P. D. Levy, A. S. Anderson, C. Arslanian-Engoren, W. B. Gibler, J. K. McCord, M. B. Parshall, G. S. Francis, et al.
Acute Heart Failure Syndromes: Emergency Department Presentation, Treatment, and Disposition: Current Approaches and Future Aims: A Scientific Statement From the American Heart Association
Circulation,
November 9, 2010;
122(19):
1975 - 1996.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. O'Rourke and W. W. Nichols
Vasodilator Therapy in Cardiac Failure: What Was New Is Old
J. Am. Coll. Cardiol.,
March 10, 2009;
53(10):
898 - 898.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. W. Yancy
Reply
J. Am. Coll. Cardiol.,
March 10, 2009;
53(10):
899 - 899.
[Full Text]
[PDF]
|
|
|
|
Top
References